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Titolo/Abstract/Parole chiave

The Endothelial Protein C Receptor enhances FVIIa mediated hemostasis

Pavani, Giulia (2014) The Endothelial Protein C Receptor enhances FVIIa mediated hemostasis. Tesi di Dottorato , Università degli Studi di Ferrara.

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    Abstract

    Recombinant activated human Factor VII (rFVIIa) is an established hemostatic agent in hemophilia but its mechanism of action remains unclear. Although tissue factor (TF) is its natural receptor, rFVIIa also interacts with the endothelial protein C receptor (EPCR) through its g-carboxyglutamic acid (Gla) domain with unknown hemostatic consequences in vivo. Here, we study whether EPCR facilitates rFVIIa hemostasis in hemophilia using a mouse model system. Murine activated FVII (mFVIIa) is functionally homologous to rFVIIa, but binds poorly to murine EPCR (mEPCR). We modified mFVIIa to gain mEPCR binding using 3 amino acid changes in its Gla-domain. The resulting molecule mFVIIa-FMR specifically bound mEPCR in vitro and in vivo and was identical to mFVIIa with respect to TF affinity and procoagulant functions. Using two macrovascular injury models in hemophilic mice, administered mFVIIa-FMR exhibited superior hemostatic properties compared to mFVIIa. These effects were specific to the mFVIIa- FMR and mEPCR interaction since antibody blocking of mEPCR abolished them. Since mFVIIa-FMR models both the TF-dependent as well as EPCR binding properties of rFVIIa, our data unmask a novel contribution of EPCR on the action of rFVIIa administration in hemophilia. This may prompt the rational design of improved and safer rFVIIa therapeutics.

    Tipologia del documento:Tesi di Dottorato (Tesi di Dottorato)
    Data:28 Marzo 2014
    Relatore:Bernardi, Francesco - Margaritis, Paris
    Coordinatore ciclo:Bernardi, Francesco
    Istituzione:Università degli Studi di Ferrara
    Dottorato:XXVI Anno 2011 > BIOCHIMICA, BIOLOGIA MOLECOLARE E BIOTECNOLOGIE
    Struttura:Dipartimento > Scienze della vita e biotecnologie
    Soggetti:Area 05 - Scienze biologiche > BIO/10 Biochimica
    Parole chiave:FVIIa, EPCR, Endothelium
    Depositato il:29 Giu 2015 12:36

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